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      Changes in Gene Expression Foreshadow Diet-Induced Obesity in Genetically Identical Mice

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          Abstract

          High phenotypic variation in diet-induced obesity in male C57BL/6J inbred mice suggests a molecular model to investigate non-genetic mechanisms of obesity. Feeding mice a high-fat diet beginning at 8 wk of age resulted in a 4-fold difference in adiposity. The phenotypes of mice characteristic of high or low gainers were evident by 6 wk of age, when mice were still on a low-fat diet; they were amplified after being switched to the high-fat diet and persisted even after the obesogenic protocol was interrupted with a calorically restricted, low-fat chow diet. Accordingly, susceptibility to diet-induced obesity in genetically identical mice is a stable phenotype that can be detected in mice shortly after weaning. Chronologically, differences in adiposity preceded those of feeding efficiency and food intake, suggesting that observed difference in leptin secretion is a factor in determining phenotypes related to food intake. Gene expression analyses of adipose tissue and hypothalamus from mice with low and high weight gain, by microarray and qRT-PCR, showed major changes in the expression of genes of Wnt signaling and tissue re-modeling in adipose tissue. In particular, elevated expression of SFRP5, an inhibitor of Wnt signaling, the imprinted gene MEST and BMP3 may be causally linked to fat mass expansion, since differences in gene expression observed in biopsies of epididymal fat at 7 wk of age (before the high-fat diet) correlated with adiposity after 8 wk on a high-fat diet. We propose that C57BL/6J mice have the phenotypic characteristics suitable for a model to investigate epigenetic mechanisms within adipose tissue that underlie diet-induced obesity.

          Synopsis

          Genetic models to explain the obesity epidemic are inadequate because the emergence of this epidemic over the past 30 y has been too rapid to allow for the appearance of new mutant genes. The authors show that diet-induced obesity among genetically identical mice is characterized by highly variable and stable phenotypes that are established in mice early in life, even before they become exposed to an obesogenic environment. Furthermore, strong associations occur between susceptibility to obesity and the expression of genes implicated in processes that regulate cellular development. Previous studies have shown that abnormal regulation of such genes by epigenetic mechanisms is linked with the development of cancer. Epigenetic mechanisms involve chemical processes that change chromatin structure and gene expression without changing the genetic code. Accordingly, epigenetic modifications of gene structure through nutritional and physiological stress provide mechanisms for inducing obesity that are independent of new mutations to the genome. Experimental models based upon genetically identical mice provide powerful tools for identifying epigenetic and environmental mechanisms causing obesity and other chronic diseases.

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          Most cited references 62

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          Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth

          Two follow-up studies were carried out to determine whether lower birthweight is related to the occurrence of syndrome X-Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia. The first study included 407 men born in Hertfordshire, England between 1920 and 1930 whose weights at birth and at 1 year of age had been recorded by health visitors. The second study included 266 men and women born in Preston, UK, between 1935 and 1943 whose size at birth had been measured in detail. The prevalence of syndrome X fell progressively in both men and women, from those who had the lowest to those who had the highest birthweights. Of 64-year-old men whose birthweights were 2.95 kg (6.5 pounds) or less, 22% had syndrome X. Their risk of developing syndrome X was more than 10 times greater than that of men whose birthweights were more than 4.31 kg (9.5 pounds). The association between syndrome X and low birthweight was independent of duration of gestation and of possible confounding variables including cigarette smoking, alcohol consumption and social class currently or at birth. In addition to low birthweight, subjects with syndrome X had small head circumference and low ponderal index at birth, and low weight and below-average dental eruption at 1 year of age. It is concluded that Type 2 diabetes and hypertension have a common origin in sub-optimal development in utero, and that syndrome X should perhaps be re-named "the small-baby syndrome".
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            Changes in energy expenditure resulting from altered body weight.

            No current treatment for obesity reliably sustains weight loss, perhaps because compensatory metabolic processes resist the maintenance of the altered body weight. We examined the effects of experimental perturbations of body weight on energy expenditure to determine whether they lead to metabolic changes and whether obese subjects and those who have never been obese respond similarly. We repeatedly measured 24-hour total energy expenditure, resting and nonresting energy expenditure, and the thermic effect of feeding in 18 obese subjects and 23 subjects who had never been obese. The subjects were studied at their usual body weight and after losing 10 to 20 percent of their body weight by underfeeding or gaining 10 percent by overfeeding. Maintenance of a body weight at a level 10 percent or more below the initial weight was associated with a mean (+/- SD) reduction in total energy expenditure of 6 +/- 3 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 5 kcal per kilogram per day in the obese subjects (P < 0.001). Resting energy expenditure and nonresting energy expenditure each decreased 3 to 4 kcal per kilogram of fat-free mass per day in both groups of subjects. Maintenance of body weight at a level 10 percent above the usual weight was associated with an increase in total energy expenditure of 9 +/- 7 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 4 kcal per kilogram per day in the obese subjects (P < 0.001). The thermic effect of feeding and nonresting energy expenditure increased by approximately 1 to 2 and 8 to 9 kcal per kilogram of fat-free mass per day, respectively, after weight gain. These changes in energy expenditure were not related to the degree of adiposity or the sex of the subjects. Maintenance of a reduced or elevated body weight is associated with compensatory changes in energy expenditure, which oppose the maintenance of a body weight that is different from the usual weight. These compensatory changes may account for the poor long-term efficacy of treatments for obesity.
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              Diet-induced type II diabetes in C57BL/6J mice.

              We investigated the effects of diet-induced obesity on glucose metabolism in two strains of mice, C57BL/6J and A/J. Twenty animals from each strain received ad libitum exposure to a high-fat high-simple-carbohydrate diet or standard Purina Rodent Chow for 6 mo. Exposure to the high-fat, high-simple-carbohydrate, low-fiber diet produced obesity in both A/J and C57BL/6J mice. Whereas obesity was associated with only moderate glucose intolerance and insulin resistance in A/J mice, obese C57BL/6J mice showed clear-cut diabetes with fasting blood glucose levels of greater than 240 mg/dl and blood insulin levels of greater than 150 microU/ml. C57BL/6J mice showed larger glycemic responses to stress and epinephrine in the lean state than AJ mice, and these responses were exaggerated by obesity. These data suggest that the C57BL/6J mouse carries a genetic predisposition to develop non-insulin-dependent (type II) diabetes. Furthermore, altered glycemic response to adrenergic stimulation may be a biologic marker for this genetic predisposition to develop type II diabetes.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                pgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                May 2006
                26 May 2006
                : 2
                : 5
                Affiliations
                [1 ] Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States of America
                [2 ] Applied Biosystems, Foster City, California, United States of America
                Stanford University, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: kozaklp@ 123456pbrc.edu
                Article
                05-PLGE-RA-0406R2 plge-02-05-13
                10.1371/journal.pgen.0020081
                1464831
                16733553
                Copyright: © 2006 Koza et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 12
                Categories
                Research Article
                Diabetes - Endocrinology - Metabolism
                Nutrition
                Genetics/Gene Discovery
                Genetics/Gene Function
                Genetics/Disease Models
                Genetics/Gene Expression
                Genetics/Epigenetics
                Eukaryotes
                Animals
                Vertebrates
                Mus (Mouse)
                Custom metadata
                Koza RA, Nikonova L, Hogan J, Rim JS, Mendoza T, et al. (2006) Changes in gene expression foreshadow diet-induced obesity in genetically identical mice. PLoS Genet 2(5): e81. DOI: 10.1371/journal.pgen.0020081

                Genetics

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